Short-Acting β-Adrenergic Antagonist Esmolol Given at Reperfusion Improves Survival After Prolonged Ventricular Fibrillation

Abstract

Background— High catecholamine concentrations are cytotoxic to cardiac myocytes. We hypothesized that myocardial interstitial catecholamine levels are greatly elevated immediately after long-duration ventricular fibrillation (VF), defibrillation, and reperfusion and that the short-acting β-antagonist esmolol administered at reperfusion would protect against this catecholamine surge and improve survival. Methods and Results— In part 1 of this study, catecholamines from myocardial interstitial fluid (ISF) and aortic and coronary sinus plasma were quantified by use of 3 H-labeled radioenzymatic assay in 8 open-chest, anesthetized pigs. Eight minutes of electrically induced VF was followed by internal defibrillation and reperfusion. By 4 minutes of VF, ISF norepinephrine increased significantly, from 1.3±0.3 to 7.4±2.4 ng/mL. Epinephrine increased significantly, from 0.4±0.2 to 1.5±0.7 ng/mL. ISF norepinephrine and epinephrine peaked at 219.2±92.1 and 63.7±25.1 ng/mL after defibrillation and reperfusion and decreased significantly to 12.2±3.5 and 6.7±3.1 ng/mL 23 minutes after defibrillation. Transcardiac catecholamine changes were similar. In part 2, 8 minutes of VF was followed by external defibrillation in anesthetized, closed-chest pigs. Animals received 1.0 mg/kg esmolol (n=8) or saline (n=8) intravenously at the start of cardiopulmonary resuscitation (CPR). Advanced cardiac life support, including CPR and epinephrine, was delivered to both groups. Esmolol before reperfusion improved return of spontaneous circulation and 4-hour survival (7/8 versus 3/8 survivors, χ 2 P <0.05). Conclusions— Transcardiac and ISF norepinephrine and epinephrine levels are briefly massively elevated after 8 minutes of VF, defibrillation, and reperfusion. A short-acting β-antagonist administered immediately after defibrillation improves return of spontaneous circulation and 4-hour survival after this prolonged VF.

Dantrolene Improves Survival After Ventricular Fibrillation by Mitigating Impaired Calcium Handling in Animal Models

“…The rise in catecholamine levels postdefibrillation 28 can result in significant stimulation of β-receptors in cardiomyocytes, impair calcium cycling by affecting ion channels such as RyR2, and result in diastolic calcium leak. Calcium leaks from sarcoplasmic reticulum in diastole will compromise the sarcoplasmic reticulum calcium reserve for subsequent beats resulting in a decrease in cardiac contractility.…”

“…8,29 The same concept can be applied to VF and refibrillation, because VF is associated with a significant increase in Ca 2+ /calmodulin-dependent protein kinase II activity (due to fast activation) and adrenergic stimulation. 28,32 Previous studies have shown that these diastolic elevations in [Ca] 2+ i depend on RyR2 activity (leak) and can result in delayed after-depolarizations and triggered activity in the endocardium specifically in Purkinje fibers. 16,26,33 Similarly, we found that VF-like activation promotes delayed after-depolarizations in our model in cardiomyocytes and Purkinje fibers, but only delayed after-depolarizations arising from Purkinje fibers could generate APDs propagating throughout the myocardium.…”

56: Beta-Blocker Use and the Changing Epidemiology of Out-of-Hospital Cardiac Arrest Rhythms

“…Several laboratory investigations suggest that beta-blockers given at the start of resuscitation efforts or after resuscitation from VF improve short term survival. (22)(23)(24)(25) However, these studies utilized cardiac electrical stimulation to induce VF in animals with normal coronary arteries and, with the exception of one study, betablockers were administered after restoration of circulation rather than before onset of arrest. It is uncertain if beta-blocker use prior to cardiac arrest will impact the effectiveness of currently recommended drugs, particularly if the beta-blocker is nonselective with an alpha-blockade effect.…”

Neuroendocrine properties of intrinsic cardiac adrenergic cells in fetal rat heart

“…Reoxygenation, compared with hypoxia, is a much more potent stimulant of myocardial catecholamine surge (18). Myocardial interstitial norepinephrine and epinephrine levels increase by severalfold during ventricular fibrillation-induced hypoxia but peak to Ͼ160 times baseline levels at the early reperfusion phase in anesthetized pigs (18).…”